三阴性乳腺癌中PI3K/AKT/mTOR信号通路的突变及相关靶向治疗的研究进展

三阴性乳腺癌（TNBC）是最具侵袭性的乳腺癌亚型,PI3K/AKT/mTOR信号通路失调是TNBC最常见的致癌突变之一,靶向PI3K/AKT/mTOR信号通路是治疗TNBC的重要方向。本文着重介绍了PI3K/AKT/mTOR信号通路的机制,TNBC中出现的PIK3CA、AKT1或mTOR的突变,以及失活张力PTEN、PIK3R1或INPP4B的突变或丢失,也展现了布帕尼西、帕他色替、依维莫司等PI3K/AKT/mTOR信号通路靶向药物在治疗TNBC中单独、联合应用和与化疗或免疫疗法联用的疗效,同时论述了目前正在进行的各类临床试验及其未来的前景。     

PI3K/AKT/mTOR信号通路介导乳腺癌内分泌治疗耐药的研究进展

内分泌治疗在激素受体阳性乳腺癌患者中的地位越来越受到重视,可以明显改善患者预后.内分泌治疗耐药严重制约着其临床应用,但耐药机制仍不明确,目前认为多信号通路激活参与耐药形成,其中PI3K/AKT/mTOR信号通路在耐药机制中发挥重要作用.临床试验提示,在内分泌治疗的基础上阻断信号通路可以逆转耐药,研究结果令人鼓舞.本文对PI3K/AKT/mTOR信号通路在内分泌耐药机制中的作用进行综述.     

PI3K/AKT/mTOR通路及其抑制剂在乳腺癌中的应用现状

磷脂酰肌醇3-激酶（phosphoinositide 3-kinase,PI3K）/蛋白激酶B（protein kinase B,AKT）/哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin,mTOR）信号转导通路在多种肿瘤中异常激活,参与肿瘤细胞增殖、分化和凋亡等生命过程的调控,是抗肿瘤药物研发的重要靶点。对目前已应用于乳腺癌临床或处于临床试验阶段的PI3K/AKT/mTOR信号通路抑制剂进行归纳,并综述该通路抑制剂的联合用药策略,以期为不同亚型乳腺癌提供个体化靶向治疗方案。     

PI3K/AKT/mTOR信号通路抑制剂治疗结直肠癌的研究进展

PI3K/AKT/mTOR通路的异常活化在结直肠癌的发生发展中起到重要作用,以此通路为靶点的药物已成为结直肠癌治疗的研究热点,临床前和临床试验研究证明,针对PI3K/AKT/mTOR通路的多种抑制剂具有抗肿瘤活性。越来越多的临床数据显示,PTEN缺乏或PIK3CA基因突变对PI3K/AKT/mTOR通路抑制剂敏感,KRAS突变则预示着耐药;寻找针对这一通路抑制剂敏感的优势人群也成为结直肠癌的研究热点;此外,PI3K/AKT/mTOR通路也会影响常规治疗的疗效,因此PI3K/AKT/mTOR通路抑制剂联合细胞毒治疗方案在结直肠癌中可能起到协同作用。     

PI3K/AKT信号通路与结肠癌细胞5-氟尿嘧啶耐药机制的关系

化疗药物耐药是影响肿瘤有效治疗的主要因素之一。5-氟尿嘧啶（5-fluorouracil,5-FU）作为一种基础化疗药物,其耐药机制成为研究热点。磷脂酰肌醇-3-激酶/蛋白激酶B（phosphatidylinositol-3-kinase/protein kinase B,PI3K/AKT）信号转导通路在促进细胞生长、运动、增殖、侵袭,抑制细胞凋亡,促进血管生成,抵抗化疗和放疗等方面起重要作用。近年来,关于PI3K/AKT信号通路与药物耐药性关系的研究越来越多,并被认为是化疗耐药治疗的新靶点。笔者查阅国内外近年来有关PI3K/AKT信号通路在结肠癌细胞5-FU耐药中作用机制的文献并做综述。     

靶向PI3K/AKT/mTOR信号通路治疗急性T淋巴细胞白血病的研究进展

急性T淋巴细胞白血病(T-ALL)是来源于胸腺T细胞祖细胞的具有强侵袭性和异质性的血液系统恶性肿瘤。T-ALL约占儿童急性淋巴细胞白血病(ALL)的15%,在成人ALL中的比例约为25%。强化化疗方案的应用使儿童T-ALL患者预后显著提高,但成人及复发耐药T-ALL患者的预后仍较差。研制新型靶向药物特异性阻断T-ALL细胞内生存及耐药相关的异常激活信号通路近年来被认为是治疗成人及复发难治T-ALL患者的新策略。PI3K/AKT/mTOR通路是T-ALL细胞内异常激活信号通路中具有代表性的一条。目前靶向该通路的多种小分子抑制剂已被成功研制,并在治疗T-ALL的研究中取得良好效果。PI3K/AKT/mTOR通路相关抑制剂较传统化疗药物具有更高的特异性和更低的毒副作用,且诸多研究表明其与低剂量化疗药物或其他靶向药物联合治疗T-ALL能发挥协同效应。本综述将总结近年来在PI3K/AKT/mTOR通路与T-ALL相关领域的研究成果,并对基于靶向该通路治疗T-ALL的研究进展一并阐述。     

PI3K/Akt/mTOR信号通路抑制剂在乳腺癌中的研究进展

目的:总结PI3K/Akt/mTOR信号通路靶向治疗在乳腺癌中的研究进展.方法:以“PI3K/Akt/mTOR、信号通路和乳腺癌”等为关键词,检索2000-01-2011-06 PubMed、Ovid和Springer等数据库的相关文献.纳入标准:1)关于PI3K/Akt/mTOR信号通路的组成、功能特点;2)PI3K/Akt/mTOR信号通路与乳腺癌的关系研究;3)以PI3K/Akt/mTOR信号通路中关键分子为靶点的乳腺癌治疗.根据纳入标准,符合分析的文献40篇.结果:信号转导通路的异常是肿瘤发生、发展的重要步骤,PI3K/Akt/mTOR信号通路与人类多种肿瘤密切相关,其在肿瘤细胞的增殖、存活、抵抗凋亡、血管发生和转移以及对放化疗抵抗中发挥了重要作用.乳腺癌中常见PI3K/Akt/mTOR信号通路的异常激活,以此通路为靶点的药物已成为乳腺癌治疗的研究热点.结论:靶向PI3K/Akt/mTOR通路中关键分子的众多药物在乳腺癌开展了一系列相关的临床试验研究,一部分显示出较好的安全性和有效性.随着对PI3K/Akt/mTOR通路的分子生物学机制的深入研究,期待靶向此通路的抑制剂将会在乳腺癌治疗中发挥巨大的作用,进一步提高乳腺癌患者的疗效和改善预后.     

抗肿瘤靶向药物引起的高血糖血症及机制

PI3K/mTOR/AKT信号转导通路是细胞信号传导的重要通路,与细胞的增殖和代谢有关,该通路异常活化可导致肿瘤细胞增殖.针对该通路研发的新型抗肿瘤靶向药物,主要不良反应为高血糖血症,高血糖血症可引起抗肿瘤药物治疗耐药.本文针对小分子靶向药物引发的高血糖血症的发生率、发生机制、表现及其处理方法作一综述.     

靶向PI3K/Akt/mTOR通路在胃癌中的研究进展

磷脂肌醇3-激酶(phosphoinositide-3 kinase,PI3K)-蛋白激酶B(protein kinase B,PKB,又称AKT)-雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)信号通路不仅与细胞的增殖、存活及迁移密切相关,其与肿瘤的发生和发展也具有相关性。近年来,以该通路作为抗肿瘤治疗的靶点已成为研究的热点。本文就胃癌中PI3K/AKT/mTOR信号通路的调节、相关蛋白的表达情况以及针对该通路的靶向药物治疗的研究作综述,并就今后胃癌中该通路可能的研究方向作展望。     

P13K／AKT／mTOR信号通路在乳腺癌Her-2治疗耐药中的作用研究进展

Her-2靶向治疗是Her-2过表达乳腺癌治疗的重要组成部分,但Her-2靶向治疗的耐药严重影响了乳腺癌的治疗。研究证实乳腺癌Her-2靶向治疗出现耐药的过程中有P13K／AKT／mTOR信号通路的激活,因此对P13K／AKT／mTOR信号通路及以P13K／AKT／mTOR信号通路为靶点的药物研究对乳腺癌治疗具有重要意义。     

Antitumor activity of pimasertib,a selective MEK 1/2 inhibitor,in combination with PI3K/mTOR inhibitors or with multi‐targeted kinase inhibitors in pimasertib‐resistant human lung and colorectal cancer cells

The RAS/RAF/MEK/MAPK and the PTEN/PI3K/AKT/mTOR pathways are key regulators of proliferation and survival in human cancer cells. Selective inhibitors of different transducer molecules in these pathways have been developed as molecular targeted anti‐cancer therapies. The in vitro and in vivo anti‐tumor activity of pimasertib, a selective MEK 1/2 inhibitor, alone or in combination with a PI3K inhibitor (PI3Ki), a mTOR inhibitor (everolimus), or with multi‐targeted kinase inhibitors (sorafenib and regorafenib), that block also BRAF and CRAF, were tested in a panel of eight human lung and colon cancer cell lines. Following pimasertib treatment, cancer cell lines were classified as pimasertib‐sensitive (IC₅₀ for cell growth inhibition of 0.001 µM) or pimasertib‐resistant. Evaluation of basal gene expression profiles by microarrays identified several genes that were up‐regulated in pimasertib‐resistant cancer cells and that were involved in both RAS/RAF/MEK/MAPK and PTEN/PI3K/AKT/mTOR pathways. Therefore, a series of combination experiments with pimasertib and either PI3Ki, everolimus, sorafenib or regorafenib were conducted, demonstrating a synergistic effect in cell growth inhibition and induction of apoptosis with sustained blockade in MAPK‐ and AKT‐dependent signaling pathways in pimasertib‐resistant human colon carcinoma (HCT15) and lung adenocarcinoma (H1975) cells. Finally, in nude mice bearing established HCT15 and H1975 subcutaneous tumor xenografts, the combined treatment with pimasertib and BEZ235 (a dual PI3K/mTOR inhibitor) or with sorafenib caused significant tumor growth delays and increase in mice survival as compared to single agent treatment. These results suggest that dual blockade of MAPK and PI3K pathways could overcome intrinsic resistance to MEK inhibition.     

非小细胞肺癌放疗抵抗研究进展

放射治疗是非小细胞肺癌的重要治疗手段之一，而肿瘤放疗抵抗限制了放疗的疗效。提高放疗疗效仍是目前非小细胞肺癌患者治疗中亟待解决的重要难题之一。研究PI3K/AKT/mTOR信号通路、肿瘤干细胞、微小RNA、HGF/c-Met、常规分割放疗等在非小细胞肺癌放疗抵抗中的作用机制，对提高非小细胞肺癌患者的生存率及改善非小细胞肺癌患者的预后具有重要意义。     

mTOR抑制剂在乳腺癌内分泌治疗耐药中的研究进展

PI3K/Akt/mTOR信号转导通路可抑制肿瘤细胞凋亡、促进细胞生存、调节细胞周期,促进肿瘤新生血管的形成以及侵袭与转移,在肿瘤的发生、发展、治疗及转归中发挥着重要作用。该信号通路与乳腺癌关系非常密切,是乳腺癌新的治疗靶点及研究热点。mTOR抑制剂通过不同的靶点作用于PI3K/Akt/mTOR信号转导通路上,从而达到其抗癌作用。内分泌治疗是乳腺癌的重要治疗方式之一,与化疗等其他治疗方式一样,内分泌治疗同样也面临治疗耐受这一难题。随着越来越多的信号通路被揭示,单一阻断某一位点已经不能满足治疗的需要,寻找多条通路的共同抑制位点成为研究人员关注的焦点。本文就mTOR抑制剂在乳腺癌内分泌治疗耐药中的作用及其临床试验结果进行综述,以期进一步了解mTOR抑制剂的临床作用。      

PI3K/AKT/mTOR信号通路在Burkitt淋巴瘤中的研究进展

 Burkitt淋巴瘤是一种高度侵袭性的非霍奇金淋巴瘤，是人类生长最快的肿瘤。根据流行病学及miRNA不同，分为地方型、散发型与免疫缺陷相关型。该病主要发生在儿童及青少年，少数发生于成年人。经短期、强效化疗后疗效显著，但成年、晚期、耐药的患者预后较差。PI3K/AKT/mTOR信号通路在细胞的生长、分化、代谢、生存以及增殖等方面发挥重要作用，研究发现，该信号通路在Burkitt淋巴瘤中呈激活状态，且针对该通路的抑制剂对Burkitt淋巴瘤细胞有抑制作用。通过对该信号通路与PTEN、c-Myc、自噬在Burkitt淋巴瘤中作用及相互关系的研究，了解其发病机制，设计该通路抑制剂与其他相关通路抑制剂或与单克隆抗体的联合用药，为晚期、耐药的患者寻找精准、高效、低毒的靶向治疗方案。     

A preclinical report of a cobimetinib-inspired novel anticancer small-molecule scaffold of isoflavones,NSC777213, for targeting PI3K/AKT/mTOR/MEK in multiple cancers

The phosphatidylinositol 3-kinase (PI3K)/protein kinase B/mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) signaling pathways are critical for normal human physiology, and any alteration in their regulation leads to several human cancers. These pathways are well interconnected and share a survival mechanism for escaping the depressant effect of antagonists. Therefore, novel small molecules capable of targeting both pathways with minimal or no toxicity are better alternatives to current drugs, which are disadvantaged by their accompanying resistance and toxicity. In this study, we demonstrate that the PI3K/AKT/mTOR/MEK is a crucial oncoimmune signature in multiple cancers. Moreover, we describe NSC777213, a novel isoflavone core and cobimetinib-inspired small molecule, which exhibit both antiproliferative activities against all panels of NCI60 human tumor cell lines (except COLO205 and HT29) and a selective cytotoxic preference for melanoma, non-small-cell lung cancer (NSCLC), brain, renal, and ovarian cancer cell lines. Notably, for NSC777213 treatment, chemoresistant ovarian cancer cell lines, including SK-OV-3, OVCAR-3, OVCAR-4, and NCI/ADR-RES, exhibited a higher antiproliferative sensitivity (total growth inhibition (TGI) = 7.62-31.50 µM) than did the parental cell lines OVCAR-8 and IGROV1 (TGI > 100 µM). NSC777213 had a mechanistic correlation with clinical inhibitors of PI3K/AKT/mTOR/MEK. NSC777213 demonstrates robust binding interactions and higher affinities for AKT and mTOR than did isoflavone, and also demonstrate a higher affinity for human MEK-1 kinase than some MEK inhibitors under clinical developments. In addition, treatment of U251 and U87MG cells with NSC777213 significantly downregulated the expression levels of the total and phosphorylated forms of PI3K/AKT/mTOR/MEK. Our study suggests that NSC777213 is a promising PI3K/AKT/mTOR/MEK inhibitor for further preclinical and clinical evaluation as a chemotherapeutic agent, particularly for the treatment of NSCLC, melanoma, and brain, renal, and ovarian cancers.     

The PI3K/AKT/mTOR Signaling Pathway: Implications in the Treatment of Breast Cancer

Epidemiologic and experimental studies support a key role of the phosphatidyl inositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway in the biology of human cancers. Alterations resulting in activation of PI3K/Akt/mTOR signaling are perhaps the most frequent events observed in solid tumors, including breast cancer, and contribute to neoplastic transformation. The PI3K/mTOR pathway can be activated by overproduction of growth factors or chemokines, loss of phosphatase and tensin homolog (PTEN) expression, or by mutations in growth factor receptors Ras, PTEN, or PI3K itself. Activation of this pathway contributes to cell cycle proliferation, growth, cell cycle entry, survival, cell motility, protein synthesis, and glucose metabolism, all important aspects of tumorigenesis. The most common genetic aberrations in breast cancer are activating somatic missense mutations in the gene encoding the p110a (PIK3CA) subunit of PI3K. The PTEN gene is often hypermethylated or decreased in expression, through as yet unclear mechanisms, in breast cancer. Studies have shown that PI3K/PTEN/AKT pathway modulation is implicated in HER2/neu-tumorigenesis and in response to the HER2-targeting antibody trastuzumab. Components of the pathway are regulated by feed-back and cross-talk to other signaling cascades and appear to be implicated with drug resistance. Over the past few years, a number of components of this signaling cascade have been the subject of intense drug-discovery activities. Rapamycin analogs have already been shown to have antitumor efficacy in some tumor types. Newer-generation PI3K, AKT, and mTOR inhibitors have shown significant promise preclinically and are now in clinical trials. This article summarizes the progress made in the elucidation of the pathway, clinical implications in pathology of breast cancer, and reviews novel drugs targeting this pathway for cancer treatment, particularly inhibitors of PI3K, AKT, and mTOR, currently undergoing clinical trials. Potential combination strategies, safety concerns, and resistance mechanisms for this new generation of anticancer agents are also discussed.     

非小细胞肺癌大分割放疗敏感性与PI3K/AKT/mTOR信号通路研究进展

常规分割放疗在中晚期非小细胞肺癌治疗中疗效有限,大分割放疗地位越来越重要,但仍有相当部分肿瘤细胞具有放射线抗拒,其分子机制未明。PI3K/AKT/mTOR信号通路与非小细胞肺癌常规分割放疗抗拒有关,但与大分割放疗抗拒关系尚未明确。调控PI3K/AKT/mTOR信号通路的基因表达及蛋白磷酸化水平有望增加NSCLC肿瘤细胞对大分割放疗的敏感性,并可能达到逆转放疗抗拒的效果;在PI3K/AKT/mTOR信号通路的诸多基因中,有望从临床样本中筛选获得预测NSCLC大分割放疗疗效的分子标记。